Cantharidic acid induces apoptosis of human leukemic HL‐60 cells via c‐Jun N‐terminal kinase‐regulated caspase‐8/‐9/‐3 activation pathway

Abstract

Cantharidin, a natural toxin from blister beetles, has shown potent anticancer activities on many solid tumor cells. Recently, cantharidin and its analogue, norcantharidin, were also shown to suppress nonsolid tumors such as chronic myeloid leukemia, acute myeloid leukemia (AML), and leukemic stem cells. However, there is no available information to address the effects of cantharidic acid (CAC), a hydrolysis product of cantharidin, on human AML cells. The present study showed that CAC, at a range of concentrations (0-20 μM), concentration-dependently inhibited cell proliferation in the HL-60 AML cell line. Western blot and flow cytometric assays demonstrated that CAC induced several features of apoptosis such as sub G1-phase cell increase, phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Moreover, treatment of HL-60 cells with CAC induced concentration- and time- dependent activation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). Only JNK-, but not p38 MAPK-specific inhibitor can reverse the CAC-induced activation of the caspase-8, -9, and -3. We concluded that CAC can induce apoptosis in human leukemic HL-60 cells via a caspases-dependent pathway, and that the apoptosis-inducing effect of CAC can be regulated by JNK activation signaling.

Coronarin D induces apoptotic cell death through the JNK pathway in human hepatocellular carcinoma

“…Many natural phytochemical products can suppress cell proliferation by arresting cells at vital phases in the cell cycle and triggering apoptosis . Our results indicated that coronarin D inhibits cell growth by inducing cell cycle arrest in the G2/M phase in human Huh7 and Sk‐hep‐1 cells (Figure A).…”

5-(Carbamoylmethylene)-oxazolidin-2-ones as a Promising Class of Heterocycles Inducing Apoptosis Triggered by Increased ROS Levels and Mitochondrial Dysfunction in Breast and Cervical Cancer

“…Our results showed that OI treatment time-dependently activated proteolytic cleavage of inactive pro-caspase-9 into its active form, whereas expression level of activated caspase-8 was unaffected (Figure 3b-d). Since the extrinsic apoptotic pathway includes caspase-8 activation, while caspase-9 is involved in the intrinsic mitochondria pathway [30], our findings prompted us to hypothesize that OI compound could activate the mitochondrial caspase-dependent apoptotic pathway, in both MCF-7 and HeLa cells.…”

“…HeLa and MCF-7 cells were maintained in DMEM-F12 medium (Sigma-Aldrich, Milan, Italy) containing 10% fetal bovine serum (FBS, Sigma-Aldrich, Milan, Italy), 2 mM L-glutamine (Sigma-Aldrich, Milan, Italy) and 1% penicillin/streptomycin (Sigma-Aldrich, Milan, Italy), as previously reported [29]. MCF-10A cells were cultured in DMEM-F12 supplemented with 10% horse serum (HS, Sigma-Aldrich, Milan, Italy) [30], 2 mM L-glutamine, 1% penicillin/streptomycin, 0.5 mg/mL hydrocortisone (Sigma-Aldrich, Milan, Italy), 20 ng/mL human epidermal growth factor (hEGF, Scheme 1. The in vitro anticancer properties of 5-(carbamoylmethylene)-oxazolidin-2-ones (OA-OI).…”

Cantharidin Induces Apoptosis and Promotes Differentiation of AML Cells Through Nuclear Receptor Nur77-Mediated Signaling Pathway

“…Cantharidin (CTD) is found to be the major bioactive component of mylabris. In recent studies, it has been found that CTD and its derivatives, such as Cantharidic acid and norcantharidin, inhibited leukemia cell proliferation, induced apoptosis, caused cell cycle arrest, and potentiated the inhibitory effects of chemotherapy drugs ( , 2001 ; Dorn et al., 2009 ; Liao et al., 2011 ; Sun et al., 2016 ; Wang et al., 2018 ). However, the potential molecular mechanisms are still not fully understood.…”